Abstract G protein-coupled receptors (GPCRs) represent the largest class of pharmacological targets in modern medicine, accounting for over 60% of all prescriptions worldwide. Yet, of the ~345 non- olfactory GPCRs, many remain either orphan (with no known ligand) or uncharacterized (with no clear physiological function). Therefore, discovering the spatiotemporal regulation and function of GPCRs within pharmaceutically- and physiologically-understudied systems is of great clinical importance. Considering the essential role of lymphatic vessels in intestinal lipid absorption and the increased prevalence of inflammatory and metabolic diseases of the intestine, it is rather remarkable that there are currently more questions than answers regarding whether and/or how lymphatic vessels contribute to normal digestive function and/or diseases in adults. Therefore, studies proposed in this grant have been purposefully designed to address numerous key questions raised by the recent NIH/NIDDK-sponsored RFA-DK-17-016 entitled: Lymphatics in Health and Disease in the Digestive System. Using state-of-the-art biochemical, proteomic, genomic and animal model approaches, we propose to build on our current expertise on the CLR-AM signaling axis within the lymphatic vascular system. Ultimately, we hope our studies will expand the repertoire of GPCR pathways that play important functions in the regulation of the neurolymphocrine unit within the GI tract, and potentially uncover unique and pharmacologically-tractable pathways for the improvement of digestive health.